Physiologically-active bases.



HEINRICH HOERLEIN, 0F ELBERFELD, 00., INC., 02' NEW YORK. N.

GERMANY, ASSIGNOR Y., A. CORPORATION OF NEW YORK.

TO SYNTHETIC PATENTS PHYSIOLOGICALLY-ACTIVE BASES.

No Drawing. Original application filedil'uly 22, 1913, Serial Specification of Letters Patent.

Patented Apr. 11, 1916.

No. 780,461.. Divided and this application filed October 29, 1915. Serial No. 58,719.

To all whom it may concern Be it known that I, HEINRICH HOERLEIN, doctor of philosophy, chemist, citizen of the German Empire, residing at Elberfeld, Germany, have invented new and useful Improvements in Physiologically-Active Bases,

of which the following is a specification.

This invention relates to a preparation of physiologically active bases which have valuable properties as a substitute for ergot, or secale preparation; and it comprises a preparation of p-oxyphenyl ethylamln havmg the formula and betaimidazolylethylamin having the formula N -cH formiof mixture of the two bases in powder render them form or of tablets or pills or of aqueous solutions of their salts, etc., all as more fully hereinafter set forth and as claimed.

This application is a division of application Serial N o. 7 80,461, filed 'July 22, 1913. It is known that preparations of ergot, or secale cornutum, as well as various substances physiological effect upon 1 the uterus and upon the blood vessels, causing their contraction; ,but the administration of these reparations shows certain disadvantages. reparation made from ergot or secale cornutum .usually contain more or less inert constituents as Well as constituents antagmented with as substitutes for secale pre rations but their use in the pure state is accompanied by such after effects as to objectionable. The be azolylethylamin when employed in thera peutical doses, frequently causes headaches, congestion of the head, erythema over the body and limbs, formication in the arms and legs, nausea, irritation of the conjuncave, palpitation of the heart, and even or bases isolated therefrom, have a' discovery has now been v marked cyanosis in consequence of temporary arrest-of respiration, convulsions and loss of consciousness, (Jaeger, Gentmlblatt fair Gymilcologz'e 1913, No. 8; Kehrer, Muench. med. Wockensckrift, No. 33, 1912).

The p-oxyphenylethylamin has the great disadvantage of acting only upon the impregnated and puerperal uterus, but not upon the virginal or quiescent uterus. The physiological eliect' of both these bases is partly antagonistioand partly synergistic.

The beta-imidazolylethylamin acts as a poison upon the automatic nervous system. tp'roducesconvulsions of the bronchial and visceral musculature, inhibition of the cardia action, relaxation of the abdominal vessels, reduction of blood pressure (in cats and humans), fall of temperature, and a tetanizing eflect upon the uterus. The last named action is supported by the direct infiuence of the beta-imidazolylethylamin upon the unstriped musculature itself, as can be demonstrated on the isolated organ, the uterine contraction being independent of the state in which the uterus may be. On the other hand, p-oxyphenylethylamin has a toxic effect upon the sympathetic nerve. It causes dilation. of the pupils and the bronchi, constriction of the blood vessels, increase of blood pressure, and contraction of the pregnant or puerperal uterus, but not of the quiescent uterus. Its action upon this organ is like that of a stimulation of the hypogastric nerve. -The remarkable bining' both bases, the. disagreeableafter-efproperties of both bases supplement each other, or in the sense of Burgis law intensify each other, so that a preparation made from these two bases forms a valuable and in many respects superior substitute for secale cornutum or its extracts. This preparation is moreover free always uterus as we puerperal the more re the para-oxyp any effect upo uterus, and may, feet, so that i animpairme the beta-imi feared.

The prep present ways an The two bases ma state in appropria may be cryst 1 proportionsprepa talliza The bases from prepa tum or they may and tyrosin by putrt which case the bases are an economical manner an be separated The prepa amin and present invent as substitutes for erg over which, however, terial advantages The proper found to giv action are abo The prepar acts both upon ll as upon been may beta-imidazo 2-3 p chlorid disso The prepara cated above in 4-30 parts the alkaloid tate with picric aci ation of the p the Virgina markable since,

henylethylami n the Virgina n the preps, nt of the con dazolylethyla-min was to invention ma (1 may exist er separately 0 tlon or in aqueous so themselves m be prepare ration of p-oxy dazolylethyla ion are intende they possess ver lready poi the two bases w bout 430 pa lamin. Thus an pared by usin lylethylamin the proport is a white pow al reaction,

n fails to exert I From the hydrochlorids the free bases 1 and quiescent may beprepared as follows: 1 part of beta have a relaxingefimidazolylethylamin -hydrochlorid and 4c ration of-both b'ases parts of p-oxyphenylethylamin-hydrochlorid tractile action of are suspended in boiling alcohol and treated be while stirring with the calculated amount of sodium ethylate. The separated salt is filof the two bases of the tered off and the alcoholic solution of the e made in various free bases is neutralized by means of phos s conditions. phoric acid. After evaporation to dryness, be used in the isolated the'residue can be used either in the powder xtures, or the bases form or in the form of tablets or pills, or allized together in the desired can be made up into solutions of the desired f the :bases may be strength.

r v in joint crys- The bases may be prepared by subjecting a mixture of histidin and tyrosin to putreay be recovered factive fermentation, as already described, or secale cornuand the resulting product or preparation of d from histidin the two bases may be used in medicine as fermentation in described above.

produced in The composition of the present invention red need. not can be administered by subcutaneous, intra r further use. venous, intramuscular, oral or rectal appliphenylethyl cation.

min of the I claim: i

d to be used 1. As a new medicinal composition, a mixor secale cornutum, ture comprising para-oxyphenylethylamin y maand beta-imidazolylethylamin characterized d out. by showing the alkaloidal reaction-and givhich have ing azo bodies with diazo compounds. desired physiological 2. As a new medicinal composition, a t of beta-imidazolylphysiologically active preparation of the rts of .p oxy two bases p-oxyphenylethylamin and betasolution imidazolylethylamin in the proportions of 0.1-0.5 parts of about 1 part of beta-imidazolylethylamin to drochlorid and 4-30 parts of p-oxyphenylethylamin. hylaminhydro- In testimony whereof I have hereunto 00 parts of Water. f the two bases indiwitnesses.

ions of 1 part to HEINRICH HOERLETN. [11. a} der which shows Witnesses:

ves a precipi- ALBERT Nouns, d bichlorid of mer- CLARIcE Eases.

resent invention cury, furnishes azo bodies with diazo coml and quiescent pounds, and is very easily soluble in water. the pregnant and Among the salts of the two bases those of This action appears all greatest importance are the ones most easily" ll known, soluble in water.

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